The objective of these studies is to explore the factors which contribute to the immunomodulatory abilities and pathogenicity of Histoplasma capsulatum in mice. To accomplish this, well-characterized systems of in vivo and in vitro humoral and cell-mediated immunity will be examined. I will determine the effect(s) that: (a) yeast cell components, (b) yeast cell filtrates, or (c) supernatants from macrophages after in vitro parasitization with H. capsulatum, might exert on immune function. Systems revealing alteration(s) in the normal immune profile will be used: (a) to characterize the cell population(s) modified by H. capsulatum, (b) to probe the biochemical nature of the molecule(s) involved, (c) to explore the changes in the susceptibility of treated mice to sublethal and lethal infection with H. capsulatum, and (d) to look for changes in either the histology of the lymphoid organs, or in cell populations found in these organs. I will also assay the immunomodulatory abilities of a number of human isolates of H. capsulatum. This information will be correlated with the pathogenicity of the various isolates in order to ascertain the significance of the immunoregulatory molecule(s) in disease pathogenesis. Finally, I will determine if specific macrophage subpopulations are selectively parasitized by H. capsulatum.